Despite advances in screening and surgical treatment, metastatic epithelial cancers, which represent about 90% of human cancers, have no known cure. Tumor regression induced by standard anti-cancer therapies does not correlate with patient survival (Brekelmans et al., 2007). Such ineffectiveness of conventional therapies has been attributed to the existence of rare malignant stem cells possessing tumor-initiating potential and maintaining tumor growth, spread, and resistance to treatment (Reya et al., 2001; Clarke et al, 2006). The existence of these cancer stem cells (CSCs) was firmly confirmed in the majority of human cancers, including those of the prostate (Collins et al., 2005; Patrawala et al., 2006; 2007; Miki et al, 2007; Rowehl et al., 2008; Klarmann et al., 2009) and colon (O'Brien et al. 2007; Ricchi-Vitiani, 2007; Todaro et al., 2007) cancers. CSCs are not only highly resistant to conventional therapies, but may actually promote cancer progression by stimulating quiescent CSCs to self-renew and repopulate the tumor with undifferentiated drug resistant cells, thereby promoting cancer progression (FIG. 1) (Bao et al., 2006; Dirks, 2006; Eramo et al., 2006; Todaro et al., 2007; Bleau et al., 2009; Tortoreto et al., 2009; Yu et al., 2012). It was recently demonstrated that treatment with 5-FU and oxaliplatin, a standard therapy for metastatic colon cancer, induced up to 30-fold enrichment of CD133+ and up to 2-fold enrichment of CD44+ cells in HT29 cell line (Dallas et al., 2009).
In many cancers, the ratio of the stem-like cells to other cancer cell types correlates with tumor aggressiveness, histologic grade and clinical outcome (Mimeault & Batra, 2010). Although metastatic progression depends on multiple factors, several CSC features make them very likely candidates to be the cause and driving force of metastasis (Visvader & Lindeman, 2009; Shen & Abate-Shen, 2011). If CSCs are the only cell population with tumorigenic potential, it is conceivable that metastases-initiating cells could have CSC capabilities, and only multipotent CSCs have inherent plasticity to survive in a foreign environment and to propagate into a heterogeneous metastatic tumor. Moreover, the most recent data shows that CSCs can differentiate to or directly participate functionally as endothelial cells, thereby directly generating the necessary vasculature for secondary tumors (Hutchinson, 2011). Stem-like cells with metastatic activity were detected recently in several types of primary and metastatic tumors and metastatic cell lines (Brabletz et al., 2005; Balic et al., 2006; Patrawala et al., 2006; 2007; Hermann et al., 2007; Aktas et al., 2009; rev. Kelly & Yin, 2008; Mimeault & Batra, 2010). Therefore, due to the extreme clinical and biological significance of the CSCs, novel strategies must be targeted to the elimination of CSCs and/or the promotion of their differentiation.
Prostate cancer (PrC) is the second leading cause of cancer death among men in Western society (Jemal, A. 2011). It is initially sensitive to androgen deprivation therapy, but more than 70% of patients face post-treatment recurrence and transition of the disease to an incurable state (van Brussel, J. P. 2003). For patients diagnosed with androgen-independent PrC, microtubule stabilizers such as Paclitaxel (Ptx; Taxol) are a first-line treatment strategy that is initially effective. However, approaches to treating chemoresistant PrC are currently lacking (Zivi, A. 2010). After the initial discovery of cancer stem cells, CSCs (Zivi, A. 2010), it became increasingly evident that tumors are organized hierarchically, containing a relatively minor (but varying) population of tumor-initiating cells and a heterogeneous majority of bulk tumor cells at different stages of maturation. In support of the CSC concept of carcinogenesis, a recent study demonstrated that the expression of several commonly used CSC markers, i.e. CD44, CD166 and ALDH-1, as well as the proportion of cells that express these markers, increases with aging (Nautiyal, J. 2012). It is an established phenomenon that aging correlates with a sharp increase in the incidence of prostate and many other cancers (Jemal, A. 2011). Accumulated knowledge clearly indicates that CSCs are responsible for tumor development, maintenance and resistance to standard treatment modalities. Thus, it has been shown for many cancer types that the tumorigenic cells expressing common CSC markers, in particular CD133 and CD44, are exceptionally resistant to conventional anti-cancer drugs (such as 5-FU, oxaliplatin, irinotecan, docetaxel and others). Moreover, the number of such cells can be significantly propagated after therapy (Bao, S. 2006; Dirks P. B. 2006; Todaro, M. 2007; Woodward, W. A. 2007; Dylla, S. J. 2008; Tortoreto, M. 2009; Bleau, A. M. 2009; Mimeault, M. 2010), which usually manifests as more drug-resistant and more aggressive recurrent and metastatic disease. It is conceivable that CSCs represent the most crucial target in the development of a new generation of anti-cancer drugs.
Therefore, due to the extreme clinical and biological significance of the CSCs, novel strategies must be targeted to the elimination of CSCs and/or the promotion of their differentiation.